Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity

Cole, David K.; Bulek, Anna; Dolton, Garry; Schauenberg, Andrea J.; Szomolay, Barbara; Rittase, William; Trimby, Andrew; Jothikumar, Prithiviraj; Fuller, Anna; Skowera, Ania; Rossjohn, Jamie; Zhu, C. G.; Miles, John J.; Peakman, Mark; Wooldridge, Linda; Rizkallah, P.J.; Sewell, Andrew K.

doi:10.1172/jci89919

Cited by 31 publications

(20 citation statements)

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“…These findings have implications for the mechanisms that control the high degree of T‐cell cross‐reactivity recently reported . One key idea, which has arisen through observations made through molecular experimentation using X‐ray crystallography and other techniques, is that the TCR–pMHC interaction is highly flexible .…”

Section: Discussionmentioning

confidence: 86%

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TCR‐induced alteration of primary MHC peptide anchor residue

et al. 2019

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The HLA‐A*02:01‐restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T‐cells‐1 (MART‐1) protein, represents one of the best‐studied tumor associated T‐cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA‐A*02:01 and TCRs from clinically relevant T‐cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5‐HLA‐A*02:01‐AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide–MHC anchoring. This “flexing” at the TCR–peptide–MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well‐studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells.

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Section: Discussionmentioning

confidence: 86%

“…Despite this conserved binding geometry, the interaction between the TCR and pMHC can be highly flexible, or even reversed . This flexibility is likely to be part of the mechanism that enables T cells to cross‐react with multiple different antigens , a property that is required for effective protective immunity .…”

Section: Introductionmentioning

confidence: 99%

TCR‐induced alteration of primary MHC peptide anchor residue

et al. 2019

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“…Nevertheless, our findings support the use of approaches similar to those used in this study to extend the knowledge of beta cell antigen-specific TCR repertoires. Moreover, it is possible that both the expansion of autoreactive T cells we observed for IGRP and an apparent preference for certain TCR α-chain genes in responses to different autoantigens reflects cross-reactivity to unknown non-self antigens44, which may be favoured by selection of T cells that bear TCRs with a moderate ability to cross-react with multiple peptides45.…”

Section: Discussionmentioning

confidence: 99%

CD8+ T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage

Fuchs

Eugster

Dietz

et al. 2017

Sci Rep

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CD8+ T cells directed against beta cell autoantigens are considered relevant for the pathogenesis of type 1 diabetes. Using single cell T cell receptor sequencing of CD8+ T cells specific for the IGRP265-273 epitope, we examined whether there was expansion of clonotypes and sharing of T cell receptor chains in autoreactive CD8+ T cell repertoires. HLA-A*0201 positive type 1 diabetes patients (n = 19) and controls (n = 18) were analysed. TCR α- and β-chain sequences of 418 patient-derived IGRP265-273-multimer+ CD8+ T cells representing 48 clonotypes were obtained. Expanded populations of IGRP265-273-specific CD8+ T cells with dominant clonotypes that had TCR α-chains shared across patients were observed. The SGGSNYKLTF motif corresponding to TRAJ53 was contained in 384 (91.9%) cells, and in 20 (41.7%) patient-derived clonotypes. TRAJ53 together with TRAV29/DV5 was found in 15 (31.3%) clonotypes. Using next generation TCR α-chain sequencing, we found enrichment of one of these TCR α-chains in the memory CD8+ T cells of patients as compared to healthy controls. CD8+ T cell clones bearing the enriched motifs mediated antigen-specific target cell lysis. We provide the first evidence for restriction of T cell receptor motifs in the alpha chain of human CD8+ T cells with specificity to a beta cell antigen.

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“…Although cancer was the main focus of this study, we have used very similar approaches to investigate T-cell responses to viruses323334353637 and during autoimmunity383940. Furthermore, we have used these techniques more broadly to understand the molecular principles that govern T-cell antigen recognition2194142.…”

Section: Discussionmentioning

confidence: 99%

Using X-ray Crystallography, Biophysics, and Functional Assays to Determine the Mechanisms Governing T-cell Receptor Recognition of Cancer Antigens

MacLachlan

Greenshields‐Watson

Mason

et al. 2017

JoVE

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Human CD8+ cytotoxic T lymphocytes (CTLs) are known to play an important role in tumor control. In order to carry out this function, the cell surface-expressed T-cell receptor (TCR) must functionally recognize human leukocyte antigen (HLA)-restricted tumor-derived peptides (pHLA). However, we and others have shown that most TCRs bind sub-optimally to tumor antigens. Uncovering the molecular mechanisms that define this poor recognition could aid in the development of new targeted therapies that circumnavigate these shortcomings. Indeed, present therapies that lack this molecular understanding have not been universally effective. Here, we describe methods that we commonly employ in the laboratory to determine how the nature of the interaction between TCRs and pHLA governs T-cell functionality. These methods include the generation of soluble TCRs and pHLA and the use of these reagents for X-ray crystallography, biophysical analysis, and antigen-specific T-cell staining with pHLA multimers. Using these approaches and guided by structural analysis, it is possible to modify the interaction between TCRs and pHLA and to then test how these modifications impact T-cell antigen recognition. These findings have already helped to clarify the mechanism of T-cell recognition of a number of cancer antigens and could direct the development of altered peptides and modified TCRs for new cancer therapies.

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Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity

Cited by 31 publications

References 0 publications

TCR‐induced alteration of primary MHC peptide anchor residue

TCR‐induced alteration of primary MHC peptide anchor residue

CD8+ T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage

Using X-ray Crystallography, Biophysics, and Functional Assays to Determine the Mechanisms Governing T-cell Receptor Recognition of Cancer Antigens

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